The pharmacological properties and therapeutic use of dextromoramide.

Abstract

The idea of preventing pain doubtless occurred to the first man who suffered it; in other words, it is as old as the world. In antiquity and in the Middle Ages men used for this purpose the juice of the mandrake, whose effects were little different from those of atropine and opium, that invaluable analgesic recommended by Paracelsus.

Details

Jean La Barre
Professor of Pharmacology and of Medical Toxicology at the University of Brussels

The idea of preventing pain doubtless occurred to the first man who suffered it; in other words, it is as old as the world. In antiquity and in the Middle Ages men used for this purpose the juice of the mandrake, whose effects were little different from those of atropine and opium, that invaluable analgesic recommended by Paracelsus.

From the Renaissance until the end of the nineteenth century, opium and the alkaloids it contains - in particular, morphine, isolated by Sertürner in 1816 - were the preferred sedatives and temperature-reducing agents. However, prolonged consumption of this alkaloid by human beings produces tolerance phenomena of such a nature that abrupt withdrawal of the drug when taken in non-toxic doses can cause serious morbid phenomena known as "abstinence symptoms".

The introduction of barbiturate therapy at the beginning of this century was a great advance, as it freed us to some extent from complete dependence on opium, which had hitherto been used as a sedative in cases of insomnia, agitation and nervous hyperexcitability.

In the special field of analgesics, further progress was achieved through the therapeutic use of synthetic substances with morphine-like properties of the pethidine and methadone groups.

Much more recently, a detailed study of certain derivatives of the propylamines has shown the powerful analgesic effect of dextromoramide, which was found to be effective against extremely violent pains frequently not allayed by normal doses of opiates.

In view of the chemical relationship between dextromoramide and other synthetic analgesics, it may be considered that this substance is, indirectly, a derivative of isomethadone in which: (1) the ethyl radical of the ketone group has been replaced by a pyrrolidine radical, and (2) the dimethylamine radical has been replaced by the morpholine radical.

The substance described by P. A. Janssen (1956) is thus really, as Castel, Attiso & Serre have pointed out, merely a variant of C.N.S. analgesic substances already described by Bockmühl & Ehrhart (1944).

Dextromoramide (I), the dextrorotatory base of 2,2-diphenyl-3-methyl-4-morpholinobutyrylpyrrolidine, may be considered as a substituted 3,3-diphenyl-propylamine (II).

The levorotatory isomer (I) has no analgesic action. It should be noted that the literature of chemistry and pharmacology describes more than one thousand substances with the same general structure (II) (Paul Janssen:
Synthetic Analgesics, Part 1: Diphenylpropylamines, Pergamon Press, 1959).

Among these substances are found not only analgesics of the morphine type, but also atropines, spasmolytics, myotropics, local anaesthetics, diuretics, general sedatives, antitussives, anti-nicotinics, etc.

As regards the analgesic and atropinic action of the drugs, the pharmacological effect of substances of type II is determined primarily by the nature of the radical R, whereas the substituents ?, ?, A and A' generally have only a quantitative influence.

1. Analgesic properties of dextromoramide

Study of the analgesic properties of new substances leads to investigation of their effectiveness and toxicity as compared with morphine and of their liability to produce addiction. Isbell recognized six groups of clearly identifiable analgesics : morphine, morphinane, pethidine, hexametylenimine, methadone and dithienylbutenylamine.

In studying the comparative pain-relieving effects of these various substances several methods have been adopted, which are briefly as follows:

The Eddy method, applied to mice, examines the time taken to react to pain, determined by placing the animal on a hot-plate kept at a temperature of 55oC.

The Ercoli & Lewis method (rat) records the time taken to react to pain caused by a hot beam of light applied to the skin of the back, which induces shuddering at the point affected.

The Haffner method (mouse) is based on the pain induced by a standardized pressure applied at the root of the tail.

The D'Amour & Smith method relies on the skin shudder produced by the application of a beam of light localized at the top of the rat's tail.

The Winder method (guinea-pig) is based on the skin shudder in response to pain caused by strong pressure on the animal's shaved back.

The method of Radouco-Thomas and collaborators (guinea-pig). This technique makes use of electro-dental stimulation of the guinea-pig's pain centres. It was used to evaluate the analgesic power of morphine and morphine-like synthetic drugs.

The Woolfe-Macdonald method (mouse) is based on the test of pain from burning the paws, which causes defensive movements in the mouse, characterized by a jump to escape.

Most of the above techniques are based on the assumption that an "effective" dose is one which prolongs the time of reaction to pain in 50 % of the animals treated.

The comparative studies we have carried out for several years have proved that the technique based on the mouse's jump to escape, following the Woolfe-Macdonald method more precisely defined by Lespagnol and his colleagues and by ourselves, produces the most satisfactory results. We base this opinion on the fact that the results obtained by this method and correlated with those for morphine hydrochloride make it possible to determine the therapeutic doses of the substance studied with the greatest accuracy, so that an analgesic effect can be produced in man, of which the intensity is exactly comparable to that previously determined for morphine.

We had an opportunity of checking the accuracy of the Woolfe-Macdonald method indirectly in the course of some experiments on the analgesic effect of UCB-2073 HCl (carbetidine).

Application of the methods of Eddy, Haffner, and D'Amour & Smith to the study of this substance had made it possible to estimate its analgesic effect as equivalent to that of morphine. Our tests by the Woolfe-Macdonald method showed that it was only half as active as morphine. Moreover, when UCB-2073 HCl (carbetidine) subsequently came to be used in clinical therapy we found that the effective dose recommended was double that of morphine, which gives indirect confirmation, in human pathology, of the correctness of the results we obtained by using the Woolfe-Macdonald method to determine its analgesic power.

Detailed Description of the Technique

Mice weighing approximately 17 to 20 g, some in normal condition and some having received fifteen minutes earlier an intravenous injection of the substance to be investigated, are placed in groups of three in a cylindrical enclosure, the thin glass floor of which is gradually and regularly heated to raise the temperature from 22o to 55o C within fifteen to twenty minutes. Determination of the mean temperature at which the jump is made is based on a simultaneous reaction by at least two out of three subjects. An electric recording thermometer is fitted with a flat electrode which is placed against the glass floor of the enclosure containing the test animals.

We carried out this investigation on several groups of white mice weighing from 17 to 20 g, comprising the following: control mouse; mouse injected subcutaneously with 0.125 mg (weak dose) of R.875; mouse injected subcutaneously with 0.250 mg (strong dose) of R.875; mouse injected subcutaneously with 1.25 mg of morphine hydrochloride.

Ten minutes were allowed to pass before beginning the Woolfe-Macdonald test.

Table 1 shows, by way of example, the results observed in three series of similar tests carried out on 300 mice.

TABLE 1

(Degrees Centigrade)

TABLE 1

(Degrees Centigrade)

Mean temperature at which the reaction to heat took place

Series

Control

R.8750.125 mg/kg

R.8750.205 mg/kg

Morphinehydrochloride1,25 mg/kg

A.

41.2°

48°

52°

52°

B.

41.8°

47°

51°

51.2°

C.

41.5°

48°

51°

52°

While the control animals make the first jump at a temperature of 41.5o, the mice given the weak dose of R.875 (0.125 mg/kg) and the strong dose (0.250 mg/kg) jump at temperatures of 48o and 52o C respectively.

Moreover, if the same type of test is made with morphine hydrochloride, in order to obtain an equal degree of insensitivity (say at 52oC) 1.25 mg/kg of this alkaloid must be administered.

Furthermore, on the basis of the work done by P. Janssen, de Jongh and their collaborators by various methods, mainly using the Eddy technique, dextromoramide, used on mice and rats, has proved to be: 8 to 36 times more active than morphine; 5 to 15 times more active than methadone; 15 to 150 times more active than pethidine; 4 times more active than diacetylmorphine (heroin).

The results observed in comparing the analgesic power of dextromoramide with that of morphine, varying as they do between 8 and 36, dearly show the lesser accuracy of the various methods (Eddy, Haffner and D'Amour) used in this research. The analgesic power of dextromoramide was confirmed by G. A. Krüger & Orth to be 32 times greater than that of morphine.

As regards the analgesic effects of dextromoramide on man, reference should be made to the work carried out in France by Boudin & Barbizet.

In his research, Barbizet used the "tingling" test, recording the occurrence of the painful reaction after immersing the hand in icy water. It may be noted that the pain-producing phenomenon in this test is attenuated more rapidly, for a longer period, and more markedly by analgesia resulting from the administration of dextromoramide than by analgesia produced by equivalent doses of morphine.

The Hewer & Ankeele test, based on pain caused by the contraction of muscles subjected to ischemia, and that of Hardy, Wolff & Goodeli, which records resistance to burning by radiant heat, both confirm Barbizet's results.

2. The action of dextromoramide on the nervous system

There are few experimental data relating to the action of strong doses of dextromoramide on the nervous system. Depending on the concentrations used, depressant effects can be observed in dogs, convulsion phenomena in rabbits, catatonic rigidity in rats, and agitation in mice,

Dextromoramide has no true narcotic properties.

According to the work of Boudin & J. Barbizet, the centre of action of dextromoramide is localized in the thalamic area and at the level of the brain stem itself.

This opinion is based on the fact that the intravenous injection of repeated doses of dextromoramide in man produces:

A lessening of thalamic pain originating in the protuberance;

Ocular clonics;

Somnolence (diencephalon);

Nausea and vomiting (medulla oblongata);

Respiratory disturbances (medulla oblongata).

Dextromoramide also appears to have a selective action on the nerve cells of the pain track, leaving the superficial sensory nerves unaffected.

3. Effect of dextromoramide on blood pressure and respiration

In tests made on rabbits we have found that dextromoramide, when given in strong doses, has a hypotensive action similar to that of morphine. It proves to be a more moderate hypotensive agent, however, with a constant and gradual effect always accompanied by bradycardia. This hypotensive effect is even more marked in animals previously subjected to narcosis by chloralose or treated with barbiturate derivatives.

The work of De Jongh & van Proosdij-Hartzema suggested that dextromoramide had relatively less depressant effect on the respiratory system than morphine. Green, resuming this work on rats, showed that the respiratory depression caused by dextromoramide was considerably more marked than that caused by morphine, and that its trend was parallel to that of the analgesic action.

It seemed to be of interest to summarize a thorough study, made with J. Dumont and J. J. Desmarez, of the depressant effect of dextromoramide on respiration, as compared with morphine, pethidine and methadone.

This study was carried out on rabbits subjected to general narcosis by intraperitoneal injection of 1 g/kg of urethan. A cannula is then inserted into the trachea and attached to a Y-tube, one branch of which is connected to a Marey respirometer, and the other to a system of Mueller valves, so that the air exhaled can be collected in a bell jar when required. At the same time a mercury manometer records the carotid blood pressure. The substances under study are injected into the auricular vein.

Control experiments have shown that rabbits thus treated maintain stable respiration and circulation for more than three hours.

Respiration is gradually reduced by injecting the analgesic in small quantities. The dose needed to depress respiratory activity by 75 % to 85 % of its initial value is determined by measuring the volume of breathing after each injection.

The average doses injected were respectively:

Mg/kg

Dextromoramide 0.25

Morphine 17.7

Pethidine 17.7

Methadone 2

The trends of the respiration and blood pressure of the rabbits under narcosis were noted during each of these experiments.

The results observed are summarized below.

TABLE 2

Product

dose with respiratory depressant effect of 80%

Time for return of breathing volume to 50% of initial figure

Hypotensive effect

Morphine.

17.7 mg/kg

Over 2.5 hours

Moderate

Pethidine.

17.7 mg/kg

Under 7 minutes

Marked

Methadone.

2 mg/kg

27 to 32 minutes

Weak

Dextromoramide.

0.25 mg/kg

27 to 32 minutes

Weak

On the basis of these results it may therefore be estimated that in rabbits treated with urethan, dextromoramide has 70 times more depressant effect on the respiration than morphine.

It is thus established by these tests, which were conducted statistically, that dextromoramide has much more depressant effect on the respiratory centre than morphine, and that great caution should consequently be exercised in using it on human beings.

In a comparative study, Rovati also observed respiration to be much more depressed by dextromoramide than by morphine administered in analgesically equivalent doses.

4. The effect of dextromoramide on intestinal motility

Like morphine and other analgesics, dextromoramide has the property of slowing the passage of food through the intestine and blocking Oddi's sphincter, though to a lesser extent than the opiates.

This problem was particularly well investigated by Green. The disturbances of the gastro-intestinal movement after the administration of analgesic doses of dextromoramide have been demonstrated by the test of Macht & Barba-Gose, which was also used by Karr in a study of cathartics.

These tests are based on determination of the rate of passage, in a rat, of a suspension containing charcoal incorporated in a test meal of constant composition.

By sacrificing the animals at different intervals after injection, the rate of progress of the charcoal through the intestine can be found.

Using this technique, Green showed that for several analgesics the rate of progress of the charcoal through the intestine was proportional to the analgesic activity of the substance tested. Consequently, the reduced rate of progress of the alimentary bolus, which is also proportional to the depression of respiration, suggests that morphine and dextromoramide exert both a central and a peripheral action on the gastrointestinal tract.

It should also be pointed out that the slowing down of the passage of foods under the influence of dextromoramide is suspended by injecting nalorphine, but prolonged by atropinization.

5. Research on the addiction-producing properties of dextromoramide

The pharmaco-dynamic study carried out by P. Janssen, de Jongh and collaborators is summarized in the work of Soupault, Caroli and collaborators. This work was done on the white rat, comparatively with morphine.

The animals received analgesically equivalent daily doses of dextromoramide (1 mg/kg) and morphine (25 mg/kg) and the analgesic effect was checked by Eddy's hot-plate method.

Under these conditions, P. Janssen noted that the analgesic effect of dextromoramide was maintained for one month with a loss not exceeding 20 %, whereas in the case of morphine the analgesic effect of the test dose disappeared completely after ten days.

Furthermore, in rats habituated to morphine, the test dose of 1 mk/kg of dextromoramide produces an analgesic effect similar to that observed in rats in normal condition.

From these tests the authors concluded that there was practically no habituation to dextromoramide after thirty days, although this phenomenon appears in ten days in subjects treated with morphine.

Moreover, the opinion of Soupault and his collaborators, based on a clinical study, seems to confirm the findings of P. Janssen on the rat. Indeed, these authors report that when the painful phenomenon shows real stability, the same doses of dextromoramide can be given almost indefinitely.

However, Vaille notes that with many patients, when treatment has to be prolonged, there is an obvious increase in tolerance, which makes it necessary to increase the dose.

He also points out that M. David & Deligne note a decrease in the intensity and duration of the side effects of dextromoramide as treatment is continued. P. de Seze and his collaborators find that the substance seems to lose its effect more quickly than the opiates, though their effectiveness is comparable.

This important problem of habituation to dextromoramide has recently been re-examined in our laboratory using a technique perfected by J. J. Desmarez in 1957.

The method is based on recording the motor activity of dogs, from which can be assessed the degree of agitation produced by abrupt withdrawal of morphine or dextromoramide from an animal habituated to either drug.

J. J. Desmarez developed this method by estimating the motor activity of a dog from hour to hour continuously, day and night, over a certain period.

For this purpose, he built an openwork cage measuring 1.10 m by 1.5 m - i.e., big enough for a dog weighing about 10 kg to live in for several days. The cage is suspended from a stand by four springs; a movable electrode, consisting of a small quantity of mercury, and a fixed copper electrode are fixed to the cage. Thus each movement of the animal causes an oscillation of the cage and consequently of the movable mercury electrode, which comes temporarily into contact with the copper electrode.

The greater the energy communicated to the mercury, that is to say, the more violent the movement of the animal, the longer the oscillations last. The mercury electrode is connected to the cathode of gas-filled triode (thyratron), and the copper electrode is connected through a very strong resistance to the negatively charged grid of this valve. The short-circuit between the grid and the cathode at each movement of the cage lights up the thyratron and closes an electromagnetic relay in the anode circuit.

By means of this electro-magnetic relay, a recording system can be operated. We first used a system of inscription on recording paper. This technique, although satisfactory, required a tiresome and necessarily approximate count after the experiment.

J. J. Desmarez consequently abandoned recording on paper in favour of a direct count of the number of closures of the relay. For this purpose he used twenty-four meters, each of which was in operation for only one hour out of the twenty-four, and a rotary switch to change the circuit as required from hour to hour. The number of short-circuits between the grid and the cathode of the valve - i.e., the number of movements of the cage - is thus counted during the first hour of the experiment by meter No. 1, the other meters remaining out of action. At the end of the first hour the rotary switch operates; meter No. 1 is stopped and meter No. 2 started. Meter No. 1 does not, of course, return to zero at this point; it shows a figure corresponding to the number of movements recorded during the first hour.

The changeover to meter No. 3 is carried out at the beginning of the third hour, and so on up to the twenty-fourth hour. At this point either the apparatus stops or the cycle of operations begins again automatically with meter No. 1, as the experimenter chooses.

Thus at the end of the twenty-fourth hour it is only necessary to read each meter in order to have a general picture of the motor activity during each of the preceding twenty-four hours.

It should be noted that this need to read the meters and re-set them at zero after twenty-four hours is determined solely by the number of meters available.

The limitations of the method depend on the oscillation period of the mobile cage, the counting rate of which the meters are capable, and the time required for the rotary switch to change the circuit.

The period of oscillation of the cage is about three cycles - i.e., the technique will show only three movements per second. Continuous activity for one minute will therefore be shown as 3 x 60 = 180 movements of the cage.

The maximum counting rate of the meters is ten equally spaced impulses per second; hence it is not a limiting factor for the method, for whereas the resolving time is 1/10 of a second, the interval between two impulses is at least 1/3 of a second. The time taken for the rotary switch to operate is of the order of 1/50 of a second and has no practical influence on the accuracy of the count.

J. J. Desmarez has already used this method to determine objectively the intensity of withdrawal phenomena during habituation to morphine and dextromoramide.

In order to carry out a complete investigation of the addiction phenomena which might occur after the administration of daily progressive doses of dextromoramide, we were obliged to subject dogs to this treatment for several months (7 to 8). We were thus able to study the phenomena which appeared in them on abrupt withdrawal of the drug and the effects of renewed administration of dextromoramide when evident agitation had been observed.

The last dose was then maintained, as if it is exceeded the dogs become sleepy and show appreciable loss of appetite. The period of observation before withdrawal was two days, during which only the number of movements per hour during the twelve hours of night were noted.

The period of withdrawal was two days, and the renewed treatment with a dose of 25 mg for a dog of 10 kg was given for one to two days.

Taking the average curves of the movements observed in the four dogs tested, we have the cumulative values shown in figure 1, which is given as an example.

On the other hand, if abstinence phenomena accompanied by a high degree of agitation are induced in animals habituated to morphine, it is easy to end these phenomena by giving 2 x 0.5 mg per kg per day of dextromoramide.

FIGURE 1

Average cumulative curves of results with 4 dogs

1 and 2 (dotted line), period of habituation to dextromoramide;

3and 4 (broken line), two days' abstinence;

5 (continuous line), period of renewed treatment with 25 mg of dextromoramide.

Ordinate: number of movements per hour;

Abscissa: time in hours. .

We have thus established the existence of habituation after daily administration of increasing doses of dextromoramide, so that it appears essential to control the clinical use of this drug on human beings most carefully

This research, in contradiction with the observations of long-lasting analgesic phenomena produced in rats by the same dose of dextromoramide, which tended to dismiss the danger of addiction, has been confirmed in clinical work by several authors.

A very well investigated case was reported by Douin, who described the establishment of very serious addiction to dextromoramide in a patient taking 40 x 5 mg tablets per day to alleviate rheumatic pains of the sciatic type. A three weeks' withdrawal programme was carried out with decreasing doses at the cost of very distressing efforts. The patient lost 8 kg during the cure, and remained depressed and aboulic for a long time.

Mendes, Dos Santos & Soeiro have reported, in a patient treated by dextromoramide for an alcoholic polyneuritis, the presence on withdrawal of habituation symptoms similar to those observed for morphine. However, the withdrawal cure was easier with dextromoramide than with the opiates.

Quite recently Boudin & Barbizet, as well as Brisset & Dereux, have reported eight observed cases in which a real addiction to dextromoramide was established.

On the other hand, Alvarez-Ude, in a clinical study, was unable to observe the occurrence of a dependence phenomenon following treatment with dextromoramide, and considers that the addiction-producing properties of the substance have not been proved. M. K. Gilles, in his thesis considering dextromoramide as an adjuvant in surgery, concludes that administration of this substance does not entail withdrawal phenomena, which goes to confirm the absence of habituation after prolonged treatment reported by Soupault and collaborators, Boudin & Barhizet, Serre and collaborators, Piulachs, and Ruggiero.

Lastly, in a study carried out by H. Fraser and Isbell at the Lexington Center (USA) at the request of the Addiction Research Center,
* these authors have demonstrated the elimination of the abstinence syndrome by dextromoramide in addicts with a stabilized consumption of 200 to 340 mg of morphine per day. Their conclusions lead them to believe that dextromoramide has addiction-producing properties at least equivalent to those of morphine.

These few clinical studies therefore provide confirmation, in human medicine, of our experimental findings, and justify in all respects the conclusions of our work, which earnestly recommended judicious regulation of the therapeutic use of dextromoramide.

6. Toxicity of dextromoramide

The first studies on the chemical toxicity of this substance, carried out on rats, mice and dogs by Janssen, indicate that in this respect dextromoramide has properties similar to those of morphine.

According to Auger, when administered to rats for five weeks in daily doses of 2.5 mg/kg, dextromoramide shows negligible toxicity. Histological tests were negative, as also were those made on dogs after five weeks of daily subcutaneous injection with 1 mg/kg of this substance.

The acute toxicity was specially studied in mice by Fr. Garcia-Valdecasas. According to this author, the lethal doses for 50 per cent of the animals observed during two days were as follows:

Morphine

Dextromoramide

Mg/kg

Mg/kg

Intravenously

200

22

Subcutaneously

470

120

Orally

610

220

According to this author it should be noted, however, that the toxicity decreases in inverse proportion to the weight of the animals. It is said to be considerably less in dogs than in mice.

We have ourselves investigated the acute toxicity of dextromoramide, using the method of Knaffl Lenz on guinea-pigs. This technique consists in finding the lethal dose per kg by slow intrajugular injection, over fifteen to twenty minutes, of 12 to 15 cc of a solution of the drug under investigation.

The action of the progressive poisoning is followed by an oscillograph recording of the heartbeats, the lethal dose being taken as the amount which produces three bands of silence on the oscillograph screen.

This report was published as an addendum to the proceedings of the XVIIIth session of the Committee on Drug Addiction and Narcotics of the National Research Center, Washington, D.C.; 21 to 23 January 1957.

Using this procedure on ten to twelve guinea pigs, we established the toxicity of each substance by determining the average lethal concentration. The results were as follows:

Mg/kg

Morphine hydrochloride (morphine base)

107

Codeine phosphate (codeine base)

108

Diacetylmorphine hydrochloride (heroin)

17

Dextromoramide

41

This leads to the conclusion that, according to these tests, dextromoramide is approximately 2 1/2 to 3 times more toxic than morphine.

Taking these results as a basis for calculating the therapeutic index, which is the relationship between the acute toxic dose (DL 100) and the analgesically equivalent dose of morphine, we arrive at the following figures:

Relative activity

Therapeutic index

Morphine

1

86

Dextromoramide

6

164

Consequently dextromoramide, although approximately three times more toxic than morphine, has a more favourable therapeutic index.

In a clinical case of gastric perforation, in which dextromoramide was injected subcutaneously in four doses of 10 mg, Bezem & Schalig witnessed the onset of a severe collapse which might have been fatal without powerful restorative treatment. These authors consider that doses greater than four injections of 10 mg per day present a real danger.

A fatal case was reported in France, in which 9 x 5 mg tablets of dextromoramide had been taken.

The unfavourable symptoms resulting from prolonged administration may be summed up as follows: vertigo, nausea, vomiting, sweating, amblyopia, angor, faintness, sleepiness, gastralgia, apnoea. They are less frequently observed in patients who are kept lying down.

7. The effects of dextromoramide on other functions

Apart from the analgesic and toxic effects, and the effects on the circulation and respiration described above, various other properties of dextromoramide have been noted, mainly in man.

This derivative of the propylamines has been found to induce myosis and salivation in the patient. It has an anti-diuretic effect which seems to be weaker than that of morphine. Like other analgesics, it shows temperature-reducing properties similar to those of morphine. When therapeutic doses are given, the passage of food through the intestine is slowed down less than by morphine, and in some cases there may be a blockage of Oddi's sphincter.

The physio-pathological studies undertaken after intensive treatment with dextromoramide have shown no toxic action on the liver (Langeron, Paget & Vincent), no marked increase in glycaemia, and no changes in the blood cells or in the composition of the cerebro-spinal fluid. Finally, as Caroli & Charbonnier have pointed out, dextromoramide intensifies the effects of the barbiturates, of certain tranquillizers, and of anaesthetics such as nitrous oxide.

8. Substances antagonistic to dextromoramide poisoning

As already mentioned in our pharmacodynamic study, in rabbits dextromoramide shows a depressant effect on the respiratory centre 70 times stronger than that of morphine. Hence it is not surprising that too sudden a resorption or too high a concentration in the blood induces apnoea. In some sensitive patients respiratory disturbances were noted after a single suppository had been taken. The authors of numerous clinical articles accordingly stress the fact that dextromoramide cannot be given on request as often as may appear necessary.

Among the substances suggested for use against dextromoramide poisoning, nalorphine must be given a special position. This antidote has the property of inhibiting or preventing the fixation and action both of morphine and of dextromoramide.

Authors such as Dobroschke, Krüger & Orth, as also Deligne & Gilles, particularly recommend nallyl-normorphine for the treatment of respiratory disturbances brought on by dextromoramide. The dose of nalorphine selected by the authors is three parts of nalorphine to four parts of dextromoramide. This counteracting effect of nalorphine against dextromoramide thus confirms the morphine-like character of the latter.

Methylethylglutarimide has also been suggested for checking the respiratory depression caused by dextromoramide.

In our laboratory, J. Dumont has made a special study of the neurostimulant action of megimide in rabbits. Animals whose volume of respiration has been reduced by dextromoramide to 15% to 20% of the initial amount show a return to 50 % of the normal volume in twenty-seven to thirty-two minutes, when given 2.5 mg/kg of methylethylglutarimide.

It must be pointed out, however, that in rabbits treated with dextromoramide a dose of 0.05 mg/kg of levallorphan produces a more lasting recovery of respiratory activity, and this substance has proved considerably more effective than methylethylglutarimide or nikethamide in combating respiratory disturbances.

9. Association of dextromoramide with analgesics and anaesthetics

Nelemans has particularly emphasized the danger of combining barbiturate therapy with treatment by dextromoramide. Respiratory complications after operations are largely attributable to previous treatment by intravenous injections based on nembutal. According to J. du Cailar, the use of dextromoramide in 360 general anaesthetic cases caused respiratory complications only four times.

Serre & Herail have also considered the association of dextromoramide with hydroxydione.

10. Use of dextromoramide in morphine withdrawal or oxycodone addiction cures

Serre, Attiso and collaborators have made a special study of this problem and shown the advantages of using dextromoramide in the withdrawal treatment of morphine addicts. The substitution can be progressive and be continued until the need for morphine has ceased. The details of this treatment still need to be specified, however. Again, Temple, Attiso & Serre have used dextromoramide successfully in treating poisoning by oxycodone hydrochloride.

11. The therapeutic uses of dextromoramide

All work published on the analgesics suitable for use in clinical therapy refer to the desire of experimenters and clinicians to find the ideal analgesic, which Pfeifer has described as follows:

"It must not become inactive as tolerance develops and must not bring on habituation or addiction. It must have a wide margin in therapy and be entirely safe to use. It must be active against every type of pain and have a short latent period and a long-lasting action. It must not affect sensory functions other than pain. It must not depress respiration or the cardiovascular system; it must not affect the gastro-intestinal tract. It must be clinically stable and inexpensive. It must be suitable for administration both orally and parenterally, and must not be antidiuretic."

It seems hardly necessary to stress the fact mentioned by Schuller that none of the synthetic or natural substances used hitherto, including dextromoramide, satisfies all these requirements.

The clinical work done so far relates to the following:

Analgesia of acute pain syndromes and painful phenomena arising in surgery and neuro-surgery;

The various studies and observations published on these subjects will now be successively considered.

A
. Analgesia of Acute Pain Syndromes and Use before, during and after Anaesthesia

Nayrac has used dextromoramide with good results in treating sciatic neuralgia, pains of the neck and arm, and headaches resulting from insufflation of gas into the ventricles. Soupault & Caroli, in a series of widely different cases ranging from biliary and nephritic colic to inflammation of the pancreas, peritonitis and minor surgery, have mentioned the remarkable and constant sedative effect of a dose of 5 mg of dextromoramide.

Boudin & Barbizet have used this drug to treat various cephalic and meningeal pains, sciaticas and spinal pains. Langeron, Haget & Vincent have confirmed these results in a large number of cases of artificially induced pain of varying intensity (vein puncture and probing). M. Gilles has described the use of dextromoramide on a large number of patients undergoing neuro-surgery both before, during and after the operation. In clinical practice (bronchoscopy and arterioscopy), in surgery (gastrectomy, nephrectomy, hysterectomy), A. Ruggiero and Diaz consider dextromoramide an analgesic of undeniable value.

In the pre- and post-operative treatment of the most diverse medico-surgical conditions, the pain-reducing properties of this propylamine derivative have been confirmed by Piulachs, by E. Cope & Jones and by Dyrberg & Andersen.

B.
The Use of Dextromoramide before, during and after Anaesthesia

The studies of David & Deligne and of Starace & Noferi conclude that dextromoramide strongly intensifies the effects of the barbiturates, and consequently does not appear suitable for use in pre-anaesthesia. In neuro-surgery the use of dextromoramide with nitrous oxide appears to give better results than the combination of nitrous oxide and pethidine.

In the post-operational period the respiratory depression caused by this analgesic makes its use definitely inadvisable.

C.
Use of Dextromoramide in treating Stubborn Pains of Neurological Syndromes and of Neoplasms

The statistics furnished by Soupault & Caroli and by Boudin & Barbizet mention the possibility, in many cases of neoplasia and radiculitis, of allaying the most violent pains which frequently will not yield to morphine. The progressive doses used may reach 400 mg orally per day, without any unfavourable consequences.

These observations have been confirmed by Roba and by Huant, who reported total suppression by dextromoramide of very intense local pains produced by a karyoklastic derivative, N-desacetylthiocolchicine.

D.
Use of Dextromoramide in Obstetrics

Several authors such as Auger, Malinas, Peeters and Sejived have sought to extend the use of dextromoramide to the field of obstetrics. They have made the following observations.

Dextromoramide has no effect on the rhythm or duration of the uterine contractions. It helps to dilate the cervix uteri, and reduces the number of difficult births, while the mother remains conscious through all the phases of the confinement.

Dextromoramide may have a harmful effect on the new born child by causing dangerous apnoea, but this may be counteracted by the use of an antidote such as nalorphine.

E.
Use o Dextromoramide in Psychiatry

The observations made by Soupault & Caroli and David & Deligne show that dextromoramide has no direct effect on the psyche and cannot be used in cases of excitation accompanied by excessive volubility. The use of this substance in nervous cases produces sensations of diffuse warmth, a tendency to slight ebriety and a very distinct euphoria, without having any direct effect on anxiety phenomena.

12. Regulation and control of the use of dextromoramide in clinical work

After it was proved that dextromoramide produced habituation in dogs and that many cases of addiction were observed in humans, Nayrac & Martin point out the frequent occurrence of euphoric phenomena: "Sense of well-being, of relaxation, slight excitement in speech. This state may sometimes be accompanied by slight ebriety, sometimes by nausea and vertigo."

Fraser and Isbell, during experiments carried out at the Lexington Hospital, noted that doses of 4 and 5 mg injected subcutaneously had an effect similar to that of small doses of morphine or pethidine. The dose of 10 mg corresponded to the effect observed for a mixture of heroin and cocaine.

When the drug is introduced orally at a concentration of 15 mg, subjective effects are much less marked and do not seem to differ greatly from those noted with the barbiturate derivatives.

The condition of dependence was also closely investigated by these authors, who report that dextromoramide suppresses withdrawal symptoms in the case of morphine and that addicts say they are better satisfied with this treatment than with the original morphine treatment.

In France, a Ministry of Public Health decree of 28 December 1957 stated that dextromoramide had been officially registered and would be put on sale under the name of "Palfium", included in list B, and sold in boxes of twenty tablets of 5 mg. It would be illegal to distribute samples to the medical and pharmaceutical professions. No publicity was to be conducted unless approved by the Ministry.

In Belgium, the authorities, basing themselves on the recommendations of the United Nations Commission on Narcotic Drugs, classed dextromoramide among the addictionproducing drugs, entered it on list 5 of the Pharmacopoeia, and placed it under control as strict as that on morphine.

General considerations and conclusions.

For some years past a number of synthetic analgesics have made their appearance which in many cases may have addiction-producing properties and thus constitute a real danger to society.

Several substances of this nature have been used for treating human beings without having first been submitted to detailed pharmacodynamic study. This was especially true of dextromoramide, where the first clinical studies made, as well as the tests carried out on rodents (rat and mouse), seemed to show that habituation did not occur in the case of this analgesic.

It is therefore extremely important that the various countries producing these new narcotics should not be permitted to distribute them locally or universally until extensive experiments have been made to prove that they are harmless and effective.

This problem has psychological and social aspects, the importance of which was stressed at the eleventh session of the Commission on Narcotic Drugs.
* The eighth report of the Expert Committee on Addiction-producing Drugs (WHO No. 142), which was issued in 1958, considers that dextromoramide produces morphine-like effects, will suppress abstinence phenomena of a known morphine addiction, and will sustain a morphine addiction. Consequently, this committee recommends that the opinion which it has expressed with respect to this substance and its isomers and salts be communicated to the Secretary-General of the United Nations.

Among the drugs based on or resembling morphine, synthetic substances of the dextromoramide type frequently produce powerful effects which are proportional to their addiction-producing qualities. From the purely therapeutic point of view it might, objectively considered, be thought that dextromoramide, in addition to its addiction-producing effect and its powerful depressant effect on the respiratory centre, has the undeniable advantage that, when administered in therapeutic doses, it has neither depressant effects on the circulation and the heart, nor constipating effects similar to those of the opium derivatives.

To get a better idea of the pharmacological characteristics of this new drug it would certainly be well to know more about its action on the various parts of the central nervous system. It is very likely that dextromoramide has depressant effects on the thalamus and the brain-stem. Though it leaves the tracks of superficial sensation completely unaffected, it definitely diminishes certain thalamic syndromes and also pains originating in the protuberance. Moreover, its use frequently induces somnolence, with its seat in the diencephalon, and, by its action on the
medulla oblongata, causes nausea, vomiting and respiratory troubles.

When we consider the pharmaceutical forms in which dextromoramide has been recommended (subcutaneous injections, tablets to be taken orally, and suppositories), we can only heartily commend the wisdom of the decision taken in France to allow it to be used only in tablet form.

Taken in other forms, the unexpectedly rapid resorption of the drug may cause the functioning of the respiratory centre to be arrested or disturbed. We have had reports of the misuse of dextromoramide in dental practice, where serious respiratory depression was noted after only one suppository had been administered.

In this connexion also we would like to take the strongest exception to the views expressed in many clinical papers to the effect that dextromoramide can be administered as often as necessary.

As a rule, posology should be very cautious, especially for the initial doses. It is advisable to make the patients lie prone for thirty minutes after taking the dose. It is also better to prescribe dextromoramide in the form of tablets, each containing a single 5 mg dose, the daily dose not to exceed 20 mg (i.e., four tablets).

It would seem rather imprudent to give dextromoramide along with barbiturate derivatives, as this may well intensify the thalamic depression.

Dextromoramide, an analgesic that is five or six times stronger than morphine, should be used only when the conventional analgesics have failed or have not been sufficiently effective. In this respect it will be used in therapeutics only for calming severe pains, particularly pains that resist any other treatment and occur in the development of certain neoplasms. In this type of incurable complaint, in addition to the desired analgesic and sedative effect, dextromoramide produces in the cancer patient a salutary feeling of well-being which, as Paracelsus said of his soothing opiate, may "bring the final consolation to the dying, rid them of their sufferings without affecting their faculties and, while not bringing their end closer, allows them to depart peacefully and blissfully towards the realms of celestial felicity ".